NR565 Week 1 Study Outline

NR565 Week 1 Study Outline Chapter 2.7.8 Chapter 2: Review of Basic Principles of Pharmacology How Drugs are Developed • Drugs are developed by pharmaceutical companies to help patients and to make money • The early part of the drug development process is called the preclinical stage • Pharmaceutical companies will identify a drug target, starting sometimes with ingredients isolated from a plant (or organism in the case of antibiotics) with desirable medicinal properties, sometimes with a molecular target identified in the body to produce the desired response, and sometimes with a disease in need of treatment. • Many drugs are examined as pharmaceutical companies seek the elusive perfect drug with just the right combination of properties. Preclinical studies are performed on cells, isolated tissues and organs, and in laboratory animals to identify promising compounds • Drugs approved by the Food and Drug Administration (FDA) must be both safe and effective and are screened by pharmacologists specializing in various aspects of drug activity. • Ideally, drugs will produce their desired effects at dosages well below those needed to produce toxicity. • During the clinical stage of new drug development, pharmaceutical companies must establish the safety and effectiveness of new products in humans. • Phase I clinical trials typically establish biological effects as well as safe dosages and pharmacokinetics in a small number of healthy patients. o During phase II clinical trials, new drugs are used to treat disease in a small number of patients and to establish the n potential of the drug to improve patient outcomes. • If the drug still looks promising, phase III clinical trials will compare the new medication to standard therapy in a larger number of patients studied by at sites across the country. • New drugs must be at least as good as, and it is hoped better than, other available therapies. Throughout the process, pharmaceutical companies work with the FDA. • After being approved by the FDA, drugs are continuously monitored through post-marketing surveillance, in which health professionals are encouraged to report adverse events, which are studied by both pharmaceutical companies and the FDA. Drug Responses • Homeostasis is the tendency of a cell, tissue, or the body not to respond to drugs but instead to maintain the internal environment by adjusting physiological processes. • Before a medication can produce a response, it often must overcome homeostatic mechanisms. • Drug effects depend on the amount of drug that is administered. o If the dose is below that needed to produce a measurable biological effect, then no response is observed; any effects of the drug are not sufficient to overcome homeostatic capabilities. o If an adequate dose is administered, there will be a measurable biological response. With an even higher dose, we may see a greater response. • At some point, however, we will be unwilling to increase the dosage further, either because we have already achieved a desired or maximum response or because we are concerned about producing additional responses that might harm the patient. • Because pharmacology is the study of substances that produce biological responses, measurement of what happens when we administer medications is important. • Two types - these responses differ in how they are measured and dictate dosing decisions to achieve the desired effect. o Quantal  Responses that may or may not occur  Ie: convulsions, pregnancy, rash, sleep, death  A quantal response to a drug is observed in a population, and is either present or absent in any single individual.  Quantal dose-response graphs plot the rate of an outcome occurrence in a population against the drug dose.  o Graded  Biological effects that can be measured continually up to the maximum responding capacity of the biological system  Most drug responses are graded • ie: changes in BP are measured in millimeters of mercury (mm Hg); HR, diuresis; bronchodilation; FEV1; pain; coma scale  Graded responses are easier to manage clinically because we can see how each patient responds to a particular dose of medication and, if appropriate, alter the dosage to achieve a greater or less response • Expression Drug Responses o Pharmacologists show the relationship between dose or concentration and drug effect using graphs that show the dose–response relationship, or dose–response curve.  Vertical axis - drug responses  Horizontal axis - concentration o Dose-response curves provide information on the relationship between dosage or concentration and responses for one more more drugs o To “read” a concentration–effect or dose– response curve, move from left to right along th e horizontal axis; this represents an increasing dosage or concentration.  At each dosage, the level of effect is shown by the vertical height of the curve. When concentration–response data are shown for two drugs or two responses on the same graph, we can compare the effects at each dose level. o Pharmacologists compare drugs and their actions in several ways, including potency, efficacy, intrinsic activity, and selectivity.  Potency is the expression of how much drug is needed to produce a biological response. • Potency describes the difference in concentration or dosage of different drugs required to produce a similar effect. Drugs that are more potent require a lower dosage or concentration to produce the same response o Efficacy expresses the ability of a drug to produce a maximum effect at any dosage. Efficacy is the expression of the maximum effect a drug can produce.  Drugs with high efficacy can produce greater effects than lower-efficacy drugs can. o Intrinsic activity is very similar to efficacy in that it represents the ability of a drug to produce a large response. Intrinsic activity, however, is used to describe the ability of a drug to produce a response once it has occupied specific receptors.  Some drugs produce the maximum receptor stimulation once they occupy receptors; their response is limited by how many drug molecules occupy receptor sites. • Drug Selectivity o An inability to tolerate the adverse effects of a medication, generally at therapeutic or subtherapeutic doses o The most reasonable way to express selectivity is as a ratio of the dose or concentration producing the undesired effect to the dose or concentration producing the desired effect. o This is the same as determining how many times the therapeutic dosage needs to be increased to produce the undesired effect. o A medication that requires one tablet to produce the desired response and does not produce undesirable effects unless five tablets are used would have a selectivity ratio of 5. o The therapeutic index is a special ratio describing drug selectivity.  The therapeutic index is the ratio of the lethal dose of a drug to the therapeutic dose of a drug.  There are some limitations to the therapeutic index: it uses death, a really unacceptable adverse effect, and it uses data from animal studies.  But the therapeutic index provides a fixed comparison for drug safety.  The therapeutic index of drugs on the market is, of course, always greater than 1; a therapeutic index of less than 1 means that the drug kills before it cures.